Reducing Surgery in Older Patients With Breast Cancer: Can ctDNA Be a Molecular Compass?
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Monitoring Breast Cancer Without Surgery in Older Patients: On the Threshold of Safe Treatment Stratification With ctDNA
Clinical Cancer Research, 2026 · DOI: 10.1158/1078-0432.CCR-25-4079 · Click to access the article →
Treating breast cancer in women aged seventy and older requires one of medicine's most delicate balances: controlling the tumor while protecting the patient from the burden of overtreatment. A new prospective study shows that circulating tumor DNA (ctDNA — circulating tumor DNA) could redefine this equation — opening the door to identifying much earlier, through a blood test alone, who can safely be monitored without surgery and who needs treatment intensification.
Why Do Older Patients Need a Different Approach?
Estrogen receptor-positive (ER+) breast cancer has a distinctive biological identity, particularly in older individuals. The chronic inflammation, altered estrogen metabolism, and suppressed immune response accompanying aging clearly distinguish both the behavior and treatment response of these tumors from those in younger patients. The concept of “de-escalation” — avoiding unnecessarily intensive treatment — has become increasingly important in oncology in recent years and is especially critical for prioritizing quality of life and safety in this age group.
Some older patients, either by their own preference or on their physicians' recommendation, choose primary endocrine therapy (pET) instead of surgery. Using drugs such as aromatase inhibitors (anastrozole, letrozole) or tamoxifen alone is a legitimate management option for these patients. Retrospective analyses have shown that this strategy is associated with a breast cancer mortality risk of only around 3% over 6 years. However, the rate of local tumor progression remains at 20%. The fundamental question is whether we can identify this 20% group in advance and intervene in time.
Far From the Center, Close to the Patient: The Study's Structure
Conducted by researchers at the University of Pittsburgh's UPMC Hillman Cancer Center, this study (NCT05914792) enrolled 43 patients between April 2022 and April 2024. Inclusion criteria were age 70 or older, histologically confirmed ER+/HER2− stage I–III breast cancer, and choosing pET rather than surgery. For ctDNA measurement, the personalized, tumor-informed multiplex PCR–next-generation sequencing (mPCR-NGS) assay Signatera (Natera Inc.) was used. Whole-exome sequencing of each patient's tumor tissue identified up to 16 somatic variants, after which an individualized assay was developed. Blood samples were collected every 3–6 months, alongside imaging (ultrasound of the breast and axilla) and patient and caregiver questionnaires.
The study's standout design feature was its decentralized structure. Of the patients, 72% came from community oncology clinics, and because most could no longer drive, their adult children accompanied them to appointments. For this reason, 70% of patients provided their blood samples at home instead of going to a clinic, using mobile phlebotomy services — including in nursing homes and assisted living facilities. This approach both facilitated participation and had the potential to reduce the burden on the healthcare system and caregivers.
How Good a Predictor Is ctDNA?
Of the 34 patients who underwent pretreatment ctDNA measurement, 32% tested positive for ctDNA; this proportion rose markedly with increasing disease burden. Clinical stage I tumors (cT1N0), however, were all ctDNA-negative regardless of tumor grade or Ki-67 level, and none of these patients experienced progression.
In competing risks regression (Fine–Gray) adjusted for age, stage, grade, and Ki-67, the association between pretreatment ctDNA positivity and progression risk was expressed as HR 30 (p=0.0011) and was statistically significant. The clinical meaning of this figure is striking: a patient who is ctDNA-positive at baseline has a 30-fold higher risk of progression than a ctDNA-negative patient.
Competing risks regression (Fine–Gray) · Carleton et al., Clin Cancer Res 2026
Month 6: A Decision Point
ctDNA dynamics were in excellent agreement with serial ultrasound imaging. Clearance status at month 6 provided the study's clearest dividing line:
▲ ctDNA-POSITIVE WITHOUT CLEARANCE
Of the patients whose ctDNA did not decline at month 6, all experienced tumor progression according to RECIST 1.1. One hundred percent.
◐ ctDNA-POSITIVE WITH CLEARANCE
Patients who were initially positive but became negative at month 6 responded consistently to pET and did not experience progression.
● ALWAYS-NEGATIVE ctDNA
No progression was observed in any patient with persistent ctDNA negativity. p=0.002.
Data source: Carleton et al., Clin Cancer Res 2026
What Do the Mutations Tell Us?
Whole-exome sequencing analyses showed that ctDNA-negative tumors were enriched for mutations associated with endocrine-sensitive luminal disease: PIK3CA (%57), GATA3 (%30), MAP3K1 (17%). In contrast, ctDNA-positive tumors carried mutations associated with endocrine nonresponse: TP53 (36%) and ARID1A (27%). Tumor mutational burden (TMB — tumor mutational burden) also tended to be higher in ctDNA-positive tumors (p=0.0508).
A particularly noteworthy finding was that, among ctDNA-positive patients who did or did not achieve clearance at month 6, the baseline ctDNA quantity did not differ significantly (p=0.79). This shows that clearance cannot be predicted from the baseline value alone and that the month 6 assessment is essential for clinical decision-making.
The Biology of Resistance: The Role of Macrophages
The study's most original scientific contribution came from correlative analyses of matched biopsy and surgical specimens from 6 patients who underwent surgery (4 responders, 2 with progression). Spatial transcriptomic sequencing (spatial transcriptomics), multiplex immunohistochemistry (multiplex IHC), and RNA sequencing were applied to these specimens.
- Increased infiltration of CD8+ and CD4+ T lymphocytes
- Marked increase in MHCII+ macrophage density
- Eradication of CD163+ immunosuppressive macrophages
- Marked reduction in cancer cell burden
- Activation of innate immunity through ROS production
- ECM remodeling and RAGE signaling
- Marked reduction in CD8+ and CD4+ T lymphocytes
- Increase in ARG1+ immunosuppressive macrophages
- CD11c+ macrophages move closer to the cancer epithelium
- Upregulation of CD109 and CD89 gene expression
- Activation of MYC, oxidative phosphorylation, and mTORC
- Increased secretion of CCL2, PTN, midkine, and LGALS9
These findings show that resistance to pET extends far beyond mutations within tumor cells. In the progressing tumor, CD11c+ macrophages move closer to the cancer epithelium and adopt an immunosuppressive, protumor phenotype. By secreting factors such as CCL2, pleiotrophin (PTN), and LGALS9, these cells disable infiltrating T lymphocytes and create conditions for cancer cell proliferation. An ESR1 mutation (D538G) was also detected in one of the two progression cases; however, the shared immunological patterns in both patients suggest that immune suppression is at least as decisive as genomic resistance mechanisms.
What Is It Like to Remain Without Surgery?
One aspect of the study that deserves attention is the patient- and caregiver-reported outcomes. Of the patients, 82% said they felt comfortable receiving treatment without surgery, while 92% expressed at least some concern that the tumor might grow. More than 80% thought that ctDNA testing could help shape their treatment plan. A pET adherence rate of 88.2% was measured. The absence of anxiety related to ctDNA results was a particularly important finding — a reassurance that reduces psychological barriers to introducing the test into routine clinical practice.
Caregivers (mostly daughters or daughters-in-law) reported a high level of caregiving burden: they said they frequently had to interrupt their daily activities. This finding further reinforces the importance of the decentralized model and home-based mobile phlebotomy that strengthened the study.
Implications for Practice in Türkiye
Breast cancer is the most common cancer among women in Türkiye, and the number of patients aged over 70 is rising rapidly as the population ages. In our clinical practice, decisions about surgery for ER+ breast cancer in this age group are shaped by comorbidities, performance status, and patient preferences.
The fact that ctDNA testing has not yet become widely established in routine clinical practice reflects the situation in Türkiye. Nevertheless, research-level use is increasing in major oncology centers. The study's most fundamental message is that, in older patients who choose primary endocrine therapy, ctDNA assessment at month 6provides additional prognostic information that standard imaging cannot offer and allows treatment decisions to be made earlier with confidence. The study's mobile phlebotomy model also offers an inspiring approach for patients in rural areas who face transportation difficulties.
DROZDOGAN Academy — Commentary and Discussion
CLINICAL CANCER RESEARCH · CRITICAL APPRAISAL
The Importance of This Study
The need for a reliable biomarker to safely continue nonsurgical management in older patients with breast cancer has long been an unanswered question in oncology. Clinicopathological parameters, and even genomic scores such as Oncotype DX, could not predict ctDNA status. This study provides some of the first prospective data showing that a personalized ctDNA assay can reflect tumor dynamics in real time and that clearance at month 6 serves as a strong prognostic marker. Progression rates of 100% in patients without clearance and 0% in persistently negative patients — the sharpness of this distinction is striking despite the small sample size.
Strengths
The study's most notable strength is its integration of tumor microenvironment analysis with clinical outcomes. The combined use of spatial transcriptomics, multiplex IHC, and RNA sequencing sheds mechanistic light on the immunological basis of pET resistance. The identification of CD11c+/ARG1+ macrophages provides a scientific basis for future combination strategies — combining endocrine therapy with macrophage reprogramming. The decentralized design and use of mobile phlebotomy strengthen ecological validity by reflecting real-world conditions, while the inclusion of patient- and caregiver-reported outcomes gives the study both a clinical and a human focus.
Limitations and Open Questions
The most critical limitation is sample size: ctDNA analysis involved 34 patients, and the correlative studies only 6. The wide confidence intervals (HR 30; 95% CI 4.4–209) require caution when interpreting the results. The nonrandomized design does not allow direct comparison of ctDNA-guided intervention with standard monitoring. The lack of an association between baseline ctDNA quantity and clearance is also interesting; it emphasizes the importance of dynamics rather than the quantitative value, while leaving unanswered which mechanism determines clearance. In addition, Signatera's sensitivity limits in low-volume early-stage disease must not be overlooked.
Implications for Clinical Practice
These data warrant discussion of ctDNA monitoring as a systematic practice alongside standard imaging in older patients who choose primary endocrine therapy. Adopting clearance at month 6 as a “decision point” offers a concrete and timely window for treatment escalation. Hypotheses such as adding a CDK4/6 inhibitor or an oral selective ER degrader in ctDNA-positive patients, or improving quality of life by reducing imaging frequency in ctDNA-negative patients, form the core of the next clinical research agenda. Nevertheless, prospective, randomized confirmation is essential before the findings of this small, single-center study become a clinical standard.
Questions for the Future
The most critical question for the coming period is whether a randomized ctDNA-guided trial can confirm these findings. A design randomizing ctDNA-positive patients to escalation with a CDK4/6 inhibitor or oral SERD, and negative patients to reduced monitoring, would produce highly meaningful data. From an immunological perspective, targeting CD11c+/ARG1+ macrophages — through CSF1R inhibition or anti-CD47 strategies — could open a new avenue for treating endocrine resistance. Combining ctDNA with less invasive platforms and conducting cost-effectiveness analyses are among the practical questions that must be answered before widespread implementation.
Scientific Sources
- Carleton N, Chang AC, Chen F et al. Use of ctDNA in older women with ER+ breast cancer to facilitate surgical de-escalation. Clin Cancer Res 2026. DOI: 10.1158/1078-0432.CCR-25-4079
- Carleton N, Nasrazadani A, Gade K et al. Personalising therapy for early-stage oestrogen receptor-positive breast cancer in older women. Lancet Healthy Longev 2022;3:e54–66.
- Van Herck Y, Feyaerts A, Alibhai S et al. Is cancer biology different in older patients? Lancet Healthy Longev 2021;2:e663–77.
- Biganzoli L, Battisti NML, Wildiers H et al. Updated recommendations regarding the management of older patients with breast cancer. Lancet Oncol 2021;22:e327–40.
- Carleton N, Abidi H, Puthanmadhom-Narayanan S et al. Omission of surgery, primary endocrine therapy adherence, and effect of comorbidity in older women with ER+ breast cancer. J Geriatr Oncol 2024;15:101679.
- Gooijer SA, Folkersma C, van Steenhoven JEC et al. Long-term outcome of sustained endocrine monotherapy for elderly breast cancer patients. Ann Surg Oncol 2023;30:1671–77.
- Tau S, Chamberlin MD, Yang H et al. Oxidative phosphorylation is a metabolic vulnerability of endocrine therapy–tolerant persister cells in ER+ breast cancer. Cancer Res 2025;85:1145–61.
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- Underhill C, Freeman J, Dixon J et al. Decentralized clinical trials as a new paradigm of trial delivery to improve equity of access. JAMA Oncol 2024;10:526–30.
- Hubbard T, Wright G, Morgan J et al. Management and outcomes for older women with early breast cancer treated with primary endocrine therapy. Breast 2024;77:103768.
This article was created using various editorial tools, including artificial intelligence. It was reviewed by human editors before publication.
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